This application proposes a double-blind clinical trial to evaluate the efficacy of N-acetylcysteine (NAC) as a relapse prevention agent for the treatment of cocaine dependence. Treatment-seeking cocaine dependent males and females, ages 18 to 70 and of all ethnic and racial backgrounds, will be given informed consent and screened for satisfactory inclusion and exclusion criteria. The study has two working hypotheses. First, NAC will decrease relapse to cocaine use, based on multiple time-to-event measures of relapse in a group of cocaine-dependent individuals with at least 7 days of confirmed abstinence from cocaine before medication initiation. Second, the NAC group will show sustained efficacy over placebo in the 4-week follow-up period after medication is discontinued. The rationale for investigating the efficacy of NAC in the treatment of cocaine addiction was initially based on animal data that pointed to perturbations of glutamatergic brain circuitry after chronic operant exposure to cocaine. NAC ameliorated glutamatergic deficits and inhibited cocaine and cue induced reinstatement of cocaine seeking behaviors. Recent preclinical work strongly suggests that NAC will be most effective as a relapse prevention agent after a brief period of abstinence from cocaine. In animals, these positive effects persist for several weeks after cessation of NAC. In a small subset of subjects entering our recent NAC trial with a few days of abstinence, both of our NAC treatment doses showed substantially longer times to relapse than placebo. We will recruit subjects being treated for cocaine dependence in two similar intensive outpatient programs. Potential subjects with UDS-confirmed abstinence after informed consent will be screened. In Stage 1, subjects will enter a one week open-label placebo phase to continue to monitor abstinence and promote adherence to taking open-label placebo twice daily and attend clinic visits. In Stage 2, subjects will be urn randomized to balance for gender, co-morbid alcohol dependence, smoking status and severity of baseline cocaine use (< or >11 days use) in the past 30 days. To test hypothesis one, subjects will participate in an eight week trial of 1200 mg of NAC twice daily or equal-appearing and smelling placebo twice daily for eight weeks with three clinic visits per week. Incentives will be directed at medication adherence and clinic attendance. Subjects will attend cognitive behavior therapy (CBT), a standardized manual driven supportive psychotherapy frequently used in addiction medication trials. Multiple time-to-event measures will plot abstinence survival analyses over the eight weeks. To test hypothesis two, NAC will be discontinued at the end of week eight and subjects will return weekly for one additional month. To our knowledge, NAC has not been evaluated for efficacy as a relapse prevention medication for cocaine addiction in humans.